Isoform B is ubiquitously expressed except in liver and thymus. The highest level is detected in heart with abundant expression in placenta and testis.

Involvement in disease

Defects in PRKAG2 are the cause of Wolff-Parkinson-White syndrome (WPWS) [MIM:194200]; also known as preexcitation syndrome. It is the second most common cause of paroxysmal supraventricular tachycardia.Defects in PRKAG2 are the cause of cardiomyopathy, familial hypertrophic type 6 (CMH6) [MIM:600858]. A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. CMH6 patients present Wolff-Parkinson-White ventricular preexcitation, enlarged myocytes without myofiber disarray, and glycogen-containing cytosolic vacuoles within cardiomyocytes.Defects in PRKAG2 are a cause of glycogen storage disease of heart lethal congenital (GSDH) [MIM:261740]; also known as phosphorylase kinase deficiency of heart or congenital nonlysosomal cardiac glycogenosis. GSDH is a rare disease which leads to death within a few weeks to a few months after birth, through heart failure and respiratory compromise.

The AMPK pseudosubstrate motif resembles the sequence around sites phosphorylated on target proteins of AMPK, except the presence of a non-phosphorylatable residue in place of Ser. In the absence of AMP this pseudosubstrate sequence may bind to the active site groove on the alpha subunit (PRKAA1 or PRKAA2), preventing phosphorylation by the upstream activating kinase STK11/LKB1.The CBS domains mediate binding to AMP, ADP and ATP. 2 sites bind either AMP or ATP, whereas a third site contains a tightly bound AMP that does not exchange. Under physiological conditions AMPK mainly exists in its inactive form in complex with ATP, which is much more abundant than AMP.

Post-translationalmodifications

Phosphorylated by ULK1; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1 and AMPK. Phosphorylated upon DNA damage, probably by ATM or ATR.